The objective of this grant is to evaluate serotonin reuptake sites (a.k.a. serotonin transporters, SERT) of the central nervous system (CNS) using F-18 labeled positron emission tomography (PET) imaging agents. Since the introduction of fluoxetine (Prozac) in 1988, the class of selective serotonin reuptake inhibitors (SSRIs), have been extensively prescribed for millions of patients with depressive, compulsive-obsessive, social phobic or other mental disorders. By blocking the reuptake sites the concentration of a neural chemical, serotonin, in the synapse is greatly increased. A substantial increase in serotonin signaling is credited for apparent symptomatic improvements. While the SSRI drugs have helped many patients, a significant segment of patients does not respond to the treatment. There is a compelling need to find a simple method to measure the drug occupancy (or the lack thereof) of the target sites in the brain of non-responders. The PET imaging methods proposed in this project are critically important for studying binding sites of psychoactive drugs and monitoring the effectiveness of such drug treatment in the living human brain. The ultimate goal of this project is to test the feasibility of the PET imaging technique for studying behavioral and emotional disorders and their treatment. A F-18 labeled serotonin transporter ligand for PET imaging will have a better chance than current ligands for widespread application due to its longer half-life and the existing infrastructure for delivering F-18 FDG for clinical studies. The hypothesis of this project is to test if a convenient PET imaging method could be utilized to quickly assess the degree of saturation of SERT sites in the brain by PET imaging. Three specific aims are proposed for this project: 1) to synthesize and to characterize of a series of F-18 biphenylthiol derivatives as serotonin transporter ligands for PET imaging studies, 2) to perform in vivo PET imaging of serotonin transporters after an iv injection of F- 18 labeled ligand in non-human primates and to measure the occupancy of SERT after a competing dose of SSRI. Additional comparison studies on several newly reported F-18 labeled agents for PET imaging of SERT will provide semi-quantitative information for selecting a suitable candidate for human study in year 3 of this project.